Biology subjects

Patial, S.

Publications and source records attributed to Patial, S..

4 recordsLinked to original sources

bioRxiv2025

Single-cell transcriptomics reveal alveolar macrophages-specific responses in single-hit ozone exposure model in mice

Alveolar macrophages (AMs), a highly plastic immune cell population, are among the first responders to the inhaled ozone (O3) and ozonized products in the lung airspaces. However, the complete understanding of how AMs respond to O3, particularly to different concentrations, remains elusive. Accordingly, we exposed C57BL/6J male adult mice to filtered air (FA), 1 ppm O3, or 1.5 ppm O3 for 3 hours. As compared to FA-exposed mice, O3-exposed mice exhibited increased recruitment of alveolar macrophages and neutrophils in the lung airspaces, which was consistent with the elevated levels of macrophage- and neutrophil-specific chemokines, i.e., MIP-2, MCP-3, and MCP-5. Next, to profile AM transcriptome from O3-exposed mice and understand the relevance of these transcriptomic changes in relation to their population heterogeneity and functionality, we performed single-cell RNA sequencing (scRNA-seq) analyses. The differentially expressed genes (DEGs) analyses on AM population identified significant changes in 1 ppm-exposed and 1.5 ppm O3-exposed mice. As compared to AMs from FA-exposed group, AMs from 1 ppm O3- and 1.5 ppm O3-exposed groups displayed enrichment of pathways including oxidative phosphorylation, EIF2 signaling, and non-canonical NF-kB signaling. Furthermore, AMs from 1 ppm O3-exposed mice showed enrichment of IL-10 signaling pathway. On the other hand, AMs from 1.5 ppm O3-exposed mice were uniquely enriched in DNA damage bypass and repair pathways. Interestingly, UMAP analyses on annotated AMs resulted in five distinct subclusters. DEGs and ingenuity pathways (IP) analyses on each subcluster revealed O3 concentration-dependent enrichment of pathways relevant to protein translation, cholesterol biosynthesis and mitochondrial biogenesis. Further analyses revealed that O3 exposure results in cluster-specific alterations to the expression of gene signatures associated with macrophage activation. Finally, AMs from 1.5 ppm O3-exposed mice displayed elevated expression of proliferation-associated gene signatures. Taken together, this study identifies O3 concentration-dependent alterations in AMs transcriptome and associated functional modulations at a single-cell resolution.

pharmacology and toxicology↗

bioRxiv2022

NLRP3 inflammasome is dispensable in methicillin resistant Staphylococcus aureus urinary tract infection

NLRP3 inflammasome is a cytoplasmic complex that senses molecular patterns from pathogens or damaged cells to trigger an innate immune defense response marked by the production of proinflammatory cytokines IL-1{beta} and IL-18 and an inflammatory death called pyroptosis. The NLRP3 inflammasome is activated in the urinary tract by a variety of infectious and non-infectious insults. In this study, we investigated the role of NLRP3 inflammasome by inducing methicillin resistant Staphylococcus aureus (MRSA) ascending UTI in WT and Nlrp3-/- mice. At 24 and 72 hpi, compared to the WT, the MRSA-infected Nlrp3-/- showed [~]100-fold lower median CFUs, although this reduction was not statistically significant. The ablation of NLRP3 did not affect MRSA-induced urinary immune defenses as indicated by the similar levels of pro-inflammatory cytokines and chemokines and the similar numbers of granulocytes in the bladder and the kidneys of WT and Nlrp3-/- mice at 24 h after MRSA infection. However, MRSA-infected Nlrp3-/- bladders, but not kidneys, showed significantly higher monocyte infiltration. The histopathological analysis of bladder and kidney sections showed similar inflammation in MRSA-infected Nlrp3-/- and WT mice. Overall, these results suggest that MRSA-induced urinary NLRP3 activity is dispensable to the host. ImportanceIndwelling urinary catheter usage increased susceptibility to methicillin-resistant Staphylococcus aureus (MRSA) urinary tract infections (UTI) which can be difficult to treat and can result in potentially fatal complications such as bacteremia, urosepsis, and shock. In this work, we examined the role of NLRP3 inflammasome in MRSA uropathogenesis. In comparison to the WT, mice deficient in NLRP3 activity showed similar MRSA burden and similar inflammation in the bladder and kidney tissues at 24 h after the experimental induction of ascending UTI. These results suggest that NLRP3 inflammasome is not involved in shaping urinary immune defenses during acute MRSA-UTI.

immunology↗

bioRxiv2021

ZFP36L1 regulates Fgf21 mRNA turnover and modulates alcoholic hepatic steatosis and inflammation in mice

Zinc finger protein 36 like 1 (ZFP36L1) enhances the turnover of mRNAs containing AU-rich elements (AREs) in their 3untranslated regions (3UTR). The physiological and pathological functions of ZFP36L1 in liver, however, remain largely unknown. To investigate the role of ZFP36L1 in liver physiology and pathology, we generated liver-specific ZFP36L1-deficient (Zfp36l1flox/flox /Cre+; L1LKO) mice. Under normal conditions, the L1LKO mice and their littermate controls (Zfp36l1flox/flox/Cre-; L1FLX) appeared normal. When fed a Lieber-DeCarli liquid diet containing alcohol, L1LKO mice were significantly protected from developing alcohol-induced hepatic steatosis and inflammation compared to L1FLX mice. Serum ALT levels were significantly increased in alcohol-fed L1FLX versus alcohol-fed L1LKO mice. RNA-Seq analysis revealed 584 differentially-expressed transcripts in L1FLX alcohol-fed mice, many of which were inflammatory mediators, compared to only 159 in alcohol-fed L1LKO mice. Most importantly, fibroblast growth factor 21 (Fgf21) mRNA was significantly increased in the livers of alcohol-fed L1LKO mice but not in the alcohol-fed control group. The Fgf21 mRNA contains three AREs in its 3UTR, and Fgf21 3UTR was directly regulated by ZFP36L1 in luciferase reporter assays. Steady state levels of Fgf21 mRNA were significantly decreased by wildtype ZFP36L1, but not by a non-binding zinc-finger ZFP36L1 mutant. Finally, wildtype ZFP36L1, but not the ZFP36L1 mutant, bound to Fgf21 3UTR ARE RNA probe. Our results demonstrate that ZFP36L1 inactivation protects against alcohol-induced hepatic steatosis and liver injury, possibly by stabilizing Fgf21 mRNA. Our findings suggest that the modulation of ZFP36L1 may be beneficial in the prevention or treatment of human alcoholic liver disease.

biochemistry↗

bioRxiv2020

Ozone exposure upregulates the expression of host susceptibility protein TMPRSS2 to SARS-CoV-2

BackgroundSARS-CoV-2, a novel coronavirus, and the etiologic agent for the current global health emergency, causes acute infection of the respiratory tract leading to severe disease and significant mortality. Ever since the start of SARS-CoV-2, also known as COVID-19 pandemic, countless uncertainties have been revolving around the pathogenesis and epidemiology of the SARS-CoV-2 infection. While air pollution has been shown to be strongly correlated to increased SARS-CoV-2 morbidity and mortality, whether environmental pollutants such as ground level ozone affects the susceptibility of individuals to SARS-CoV-2 is not yet established. ObjectiveTo investigate the impact of ozone inhalation on the expression levels of signatures associated with host susceptibility to SARS-CoV-2. MethodsWe analyzed lung tissues collected from mice that were sub-chronically exposed to air or 0.8ppm ozone for three weeks (4h/night, 5 nights/week), and analyzed the expression of signatures associated with host susceptibility to SARS-CoV-2. ResultsSARS-CoV-2 entry into the host cells requires proteolytic priming by the host-derived protease, transmembrane protease serine 2 (TMPRSS2). The TMPRSS2 protein and Tmprss2 transcripts were significantly elevated in the extrapulmonary airways, parenchyma, and alveolar macrophages from ozone-exposed mice. A significant proportion of additional known SARS-CoV-2 host susceptibility genes were upregulated in alveolar macrophages and parenchyma from ozone-exposed mice. ConclusionsOur data indicate that the unhealthy levels of ozone in the environment may predispose individuals to severe SARS-CoV-2 infection. Given the severity of this pandemic, and the challenges associated with direct testing of host-environment interactions in clinical settings, we believe that this mice-ozone-exposure based study informs the scientific community of the potentially detrimental effects of the ambient ozone levels determining the host susceptibility to SARS-CoV-2.

pharmacology and toxicology↗